P571: ORAL AZACITIDINE VS MIDOSTAURIN AS MAINTENANCE TREATMENT FOR FLT3 MUTANT ACUTE MYELOID LEUKEMIA IN COMPLETE REMISSION: AN INDIRECT TREATMENT COMPARISON
Authors: E. N. Oliva, C. Chen, S. N. Rahim, B. Seuro, A. Vasconcelos, L. Gaugler, B. Skikne, T. Prebet, H. Cameron, C. Beach, G. Thompson
Journal: HemaSphere (2022)

Background: Patients (pts) with FLT3-mutant (mut) acute myeloid leukemia (AML) have a high risk of relapse, poor prognosis, and limited treatment (tx) options. A trend toward improved survival with oral azacitidine (Oral-AZA) vs placebo (PBO) as maintenance treatment (MT) was observed in pts in first complete remission (CR) after intensive chemotherapy (IC) induction ± consolidation in an exploratory analysis of the phase 3 QUAZAR AML-001 study (QUAZAR; NCT01757535). Midostaurin (MIDO) plus chemotherapy was FDA-approved as induction and consolidation tx for pts with FLT3-mut AML based on results of the phase 3 RATIFY study (NCT00651261); absence of randomization prior to MT makes inferences about the effectiveness of MIDO as MT difficult, although MIDO was EMA-approved for MT. The relative efficacy of MT with Oral-AZA vs MIDO has not been compared directly in clinical trials. Aims: To compare the survival outcomes of MT with Oral-AZA vs MIDO in pts with FLT3-mut AML who achieved first CR after IC (± consolidation tx) by performing an indirect tx comparison (ITC) of data from QUAZAR and RATIFY. Methods: An ITC of overall survival (OS) and relapse-free survival (RFS) comparing Oral-AZA vs MIDO was performed, in which data from QUAZAR pts with FLT3-mut AML who had achieved a CR with full blood count recovery (matching RATIFY eligibility criteria) were compared with efficacy outcomes from the RATIFY MT phase (Larson RA, et al. Leukemia 2021). Primary analyses utilized the anchored Bucher method, which assumes the relative tx effect is comparable across studies with similar effect modifiers. Time-varying methods (parametric and spline models) were also explored to account for violation of the proportional hazards (PH) assumption. Results: Of 472 pts in the intent-to-treat population of QUAZAR, 56 pts with FLT3-mut AML achieving a CR (Oral-AZA, 24; PBO, 32) were included in the primary analysis population, as were all 205 RATIFY MT-phase pts (MIDO, 120; PBO, 85). In the QUAZAR and RATIFY populations, respectively, mean age was 66.4 and 42.7 y, 55% and 50% were female, 36% and 29% had point mutations in the FLT3 tyrosine kinase domain, 0% and 57% had favorable cytogenetic risk, and 0% and 5% underwent stem cell transplantation during first CR. Bucher ITCs of both OS and RFS appeared to favor Oral-AZA over MIDO, but were not statistically significant (Table). To assess age imbalance (QUAZAR pts were ≥ 55 y; RATIFY pts, 18–59 y), an exploratory analysis with QUAZAR pts (n = 9; age-matched to RATIFY pts) showed OS and RFS results with Oral-AZA vs PBO were similar to those of all QUAZAR pts. Evidence suggests the PH assumption had been violated in some of these analyses, so best fitting parametric models were explored. Landmark OS and RFS rates (generalized gamma model) were found to be higher with Oral-AZA than MIDO (Table). Similar results were obtained using a spline model. Image:Summary/Conclusion: Despite more favorable prognostic factors among pts in RATIFY (eg, younger age), the Bucher ITC analysis showed a trend toward longer OS and RFS with Oral-AZA vs MIDO as MT for pts with FLT3-mut AML. Analyses that accounted for the PH assumption violation also indicated a survival benefit for Oral-AZA vs MIDO. Limitations included trial differences and small sample size. More research is needed to support this observation.